1. Field of the Invention
The extra corporeal treatment of blood to remove immunoglobulins and circulating immune complexes has proven useful in certain circumstances. For example, it is suspected that some cancer patients develop a particular immune complex consisting of the patient's own IgG and an antigen associated with the cancer. It is thought that such complexes can interfere with the functioning of the patient's immune system and prevent the immune system from responding to the cancer. Treatment of various cancers, including carcinomas and melanomas, using extra corporeal plasma perfusion with protein A and Staphylococcus aureus to remove immune complexes has yielded varying levels of success. The extra corporeal removal of IgG and immune complexes has also been beneficial in the treatment of certain immune system disorders, such as thrombotic thrombocytic purpura.
Human immunodeficiency virus-1 (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), has the property of infecting selected cells of the immune system and abrogating their function. The clinical course of HIV-1 infection often consists of a prolonged asymptomatic state, followed by severe depletion of T4.sup.+ helper lymphocytes, rendering the patient highly susceptible to opportunistic infections and neoplasms. HIV-1 infection can also cause a profound degeneration of the central nervous system. The variable course of HIV-related disease may reflect the complex life cycle of the virus now known to include both latent and lytic states in T4.sup.+ lymphocytes under the control of viral genes, as well as a state of limited replication in monocytes and macrophages.
The Centers for Disease Control estimate that there are now one to 1.5 million HIV-infected individuals in the United States who are asymptomatic. Studies of risk groups known to have been infected with HIV-1 for five or more years suggest that 30% of infected individuals will develop AIDS, that 10-15% of these individuals will develop AIDS related conditions (ARC), and that 10% of these individuals will develop chronic neurological disabilities. This translates into a projection of approximately 270,000 cumulative cases of AIDS by 1991, although some estimates run as high as 700,000 cases.
It is generally accepted that development of a vaccine is crucial to containment of the HIV-1 epidemic. However, assuming that a safe vaccine could be developed which confers immunity against all strains and types of HIV-1, it would not likely be available for 5-10 years. Moreover, it is uncertain that such a vaccine would be of any value in preventing development of AIDS in those individuals already infected with HIV-1.
Thus, even if an effective vaccine is developed, treatments to inhibit the progression of HIV-1 infection to AIDS and therapies for controlling opportunistic infections, neoplasms, and underlying HIV-1 infection will still be necessary.
Proposed strategies for treatment of HIV-1 infection include inhibition of viral replication and restoration of impaired immune function. Strategies for suppression of viral replication include development of monoclonal antibodies which block binding of virus to target cells and drugs which block reverse transcription of viral RNA, transcription of viral DNA, translation of viral mRNA, and virus assembly.
The most widely studied current therapy utilizing the DNA chain terminator azidothymidine (AZT) shows some promise, but has substantial toxicity which may limit its use. Restoration of immunity has been attempted by bone marrow transplantation and lymphocyte transfusion, by lymphokine administration, and by immunostimulatory drugs. While some reconstitution of cellular and humoral functions have been obtained with such treatments, HIV-1 infections have not been reversed and the course of AIDS has not been obviously altered.
It is somewhat paradoxical that persons with HIV-1 infection and progressive disease in fact produce neutralizing antibodies against HIV-1. The reason that these naturally-developing antibodies offer little protection is unclear although several plausible mechanisms have been suggested. First, the immunodominant regions of the viral envelope glycoprotein gp120 are known to lie outside the regions of viral attachment and penetration, and there is much variability in the immunodominant regions among different viral strains. Since multiple strains of HIV-1 are often found within a single individual, some strain selection or differentiation may occur in vivo. Additionally, much of the HIV-1 population may exist in a latent form in vivo where viral antigens are not expressed. Otherwise, adequate cell-mediated cytotoxic antibody dependent and/or complement dependent antibody mediated cytotoxic responses would be likely effective against such virus infected cells. Finally, HIV-1 infected cells may escape immune recognition by capping off their antigens.
It would therefore be desirable to develop a therapy which could provide long-term benefits for HIV-1 infected patients. The therapy should be able to restore the patient's immune activity and direct it against the intrinsic strains of HIV-1. Sustained protective immunity directed against an array of viral antigenic determinants favors successful challenge of different viral strains as they are activated from latently infected cells.
2. Description of the Relevant Art
Heat and formalin-treated Staphylococcus aureus Cowan I packed in a column has been employed as a therapy for neoplastic disease based on the removal of immune complexes from blood. See, e.g., Bansal et al. (1978) Cancer 42:1-18; Terman et al. (1981) N. Engl. J. Med. 305:1195-1200; Jones et al. (1980) Cancer 46:675-684; Ray et al. (1980) Cancer 45:2633-2638; Besa et al. (1981) Am. J. Med. 71:1035-1040 Holohan et al. (1982) Cancer Res. 42:3663-3668; Messerschmidt et al. (1982) Cancer Treat. Rep. 66:2027-2031; MacKintosh et al. (1983) West. J. Med. 139:36-40; Snyder et al. (1982) J. Immunol. 128:2726-2730; and Jones et al. (1984) J. Biol. Resp. Mod. 3:286-292. Terman et al. (1981) N. Engl. J. Med. 305:1195-1200 describes use of an immunoadsorbent consisting of protein A entrapped within a charcoal matrix for treatment of cancer patients. Messerschmidt et al. (1988) J. Clin. Oncol. 6:203-212 is a review of the treatment of neoplastic diseases by extra corporeal plasma perfusion. Feline leukemia virus (FeLV) infection in cats has been successfully treated by extra corporeal removal of immune complexes using S. aureus protein A columns. See, e.g., Jones et al. (1980) Cancer 46:675-684; Snyder et al. (1982) J. Immunol. 128:2726-2730; and Jones et al. (1984) J. Biol. Resp. Mod. 3:286-292. The treatment of autoimmune diseases by protein A plasma perfusion has been previously described. Korec et al. (1984) J. Biol. Resp. Mod. 3:330-335 and (1986) Clin. Oncology 4:210-215 describe the treatment of patients suffering from thrombotic thrombocytic purpura (an autoimmune disease) by extra corporeal removal of IgG and immune complexes in an agarose-protein A column. Nilsson et al. (1981) Blood 58:38-44 describes the extra corporeal removal of anti-factor IX antibodies using an agarose-protein A column. A portion of the experimental work reported in the present application was published in Kiprov et al. (1984) J. Biol. Resp. Mod 3:341-346 and is disclosed in grandparent U.S. Pat. No. 4,681,870. Other portions of the experimental results have been published in Messerschmidt et al. (1988) J. Clin. Oncol. 6:203-212; Kiprov et al. (1986) J. Clin. Apheresis 3:133-139; Mehta et al. (1986) Clin. Res. 34:501A; Snyder et al. (1987) Artif. Organs 11:334; and Snyder et al. (1988) Proc. IVth. International Conference on AIDS 1:194.